Pancreatic cancer is the ninth most common form of cancer, yet it is the fourth and fifth leading cause of cancer deaths in men and women, respectively. The most common symptoms of the disease are nonspecific in nature. Thus diagnosing pancreatic cancer at an early stage of tumor growth is difficult at best, requiring considerable suspicion and extensive diagnostic workup, up to and including exploratory surgery. Unfortunately then, the vast majority of patients present at a stage when the tumor has extended outside of the capsule to invade surrounding organs, and/or has metastasized extensively. Treatment procedures currently available for pancreatic cancer have not been able to bring about a cure nor substantially improve survival time. The consequence is a 5-year survival rate of less than 3 percent. The long-term objective of this research proposal is the development of monoclonal antibodies for the management of pancreatic cancer (i.e., detection, diagnosis, staging and therapy). We have characterized the PAM4 monoclonal antibody, providing evidence as to its use clinical detection of pancreatic cancer. A general issue in considering the use of radiolabeled antibody as a therapeutic agent for clinical application is that tumor accretion of antibody has been low compared to that achieved in experimental models. In the current research project, we will attempt to overcome this problem by investigating methodologies designed to increase tumor uptake of radiolabeled antibody while maintaining high tumor-nontumor ratios. We will engineer PAM4 antibody constructs having appended peptide signal sequences for internalization and intracellular trafficking. These will be examined to determine which of several organelle trafficking signals provides the highest tumor uptake and retention of antibody targeted radioisotope. In addition, we will examine the role of valence for homofunctional and heterofunctional organelle retention signals appended to the antibody. Finally, a PAM4IL2 fusion protein will be examined for its ability to enhance tumor uptake of a subsequently administered radiolabeled PAM4 antibody.